Lubricant Coating for Medical Container

ABSTRACT

The invention relates to a lubricant coating for a medical container comprising a cross-linked lubricant composition comprising a mixture of non-reactive silicone with reactive silicone, characterized in that the reactive silicone comprises a mixture of vinyl-based silicone and acrylate-based silicone. The invention further relates to a lubricant composition usable as an intermediate product in the fabrication of a lubricant coating. The invention further relates to a medical container comprising a barrel and a stopper in gliding engagement within the barrel, comprising such a lubricant coating. The invention also relates to a process of manufacturing a medical container comprising a barrel and a stopper in gliding engagement within the barrel including depositing a lubricant composition on the inner surface of the barrel and/or on the stopper, and irradiating the coated barrel and/or stopper so as to cross-link the lubricant composition to form a lubricant coating.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/399,192, filed Nov. 6, 2014, which is the United Statesnational phase of International Application No. PCT/EP2013/059531 filedMay 7, 2013, and claims priority to European Patent Application No.12305508.9 filed May 7, 2012, the disclosures of which are herebyincorporated in their entirety by reference.

FIELD OF THE INVENTION

The invention relates to a lubricant coating and a lubricant compositionfor a medical container and a medical container comprising such acoating.

TECHNICAL BACKGROUND

Medical containers comprising a stopper in gliding engagement within abarrel are widely used to deliver drug to patients.

Such containers include syringes, cartridges and auto-injectors.

They are preferably prefilled in order to be more easily used by apatient or by medical staff, and to eliminate the risk of contaminationthat occurs when a drug is transferred from a vial to an injectiondevice.

Such medical containers are usually lubricated to ensure a good glidingmovement of the stopper within the barrel when the drug is injected to apatient.

The gliding movement of the stopper involves the application of anactivation force to put the stopper in motion, then of a gliding forceto maintain the motion of the stopper.

In order to have a smooth gliding and to avoid any stick-slip effect,the activation force and gliding force have to be as low as possible.

Lubricant may consist in mineral or vegetable oil or in a syntheticlubricant.

Silicone oil such as poly-(dimethylsiloxane) is widely used as lubricantfor such applications.

However, such silicone oil has the drawback of being unstable over timeand especially after autoclave treatments that are usually performed toensure the sterility of the medical container, before or after thefilling of the medical containers with pharmaceutical compositions.

Due to ageing or to such treatments, it is common to observe squeeze-outof the lubricant under the pressure exerted between the stopper and thebarrel.

However, if the lubricant squeezes-out i.e. migrates from the interfacebetween the stopper and the barrel, the activation force of the stopperbecomes higher and does not allow for a smooth gliding of the stopper.

The accuracy of the delivered dose of a pharmaceutical solutioncontained into the medical container is therefore decreased particularlywhen the injection is performed by a pump.

Document EP 0 920 879 proposes a lubricant composition consisting of amixture of non-reactive silicone oil and reactive silicone, namely avinyl-based silicone, with a fraction of non-reactive silicone in themixture comprised between 5 and 85% by weight.

The composition is then applied to a medical container and subjected toa cross-linking treatment.

As a result, the coating forms a solid film along the inner wall of thebarrel.

However, such a coating still presents poor mechanical performances,i.e. high activation and gliding forces.

In particular, the activation force remains higher than the maximumdesired limit.

BRIEF DESCRIPTION OF THE INVENTION

A goal of the invention is to provide a lubricant coating for medicalcontainers that does not present the drawbacks of the known coatings.

More precisely, this lubricant coating should provide better glidingproperties, have a good stability to sterilization treatments and a goodstability over time (including a storage time comprised between 12 to 24months).

In addition, the lubricant coating should not interact with thepharmaceutical composition that is intended to be filled into themedical container.

In particular, the lubricant coating should not contain elements thatcould be extracted to the pharmaceutical composition stored in thecontainer.

A goal of the invention is to provide a lubricant composition that canbe used as an intermediate product in the fabrication of such alubricant coating.

According to an embodiment, the invention provides a lubricant coatingfor a medical container comprising a cross-linked lubricant compositioncomprising a mixture of non-reactive silicone with reactive silicone,wherein the reactive silicone comprises a mixture of vinyl-basedsilicone and acrylate-based silicone.

“Reactive silicone” means a silicone polymer comprising at least onereactive functional group, i.e. a functional group that polymerizesunder usual conditions of irradiation (e.g. Gamma or UV irradiation). Areactive functional group thus usually comprises at least one chemicalbond that is able to break under irradiation and to link up with anotherfunctional group for creating a polymer.

“Non-reactive” silicone means a silicone polymer that only comprisesnon-reactive functional groups, i.e. functional groups that do notpolymerize under usual conditions of irradiation, and that does notcomprise any reactive functional group as defined above. For example,linear alkyl chains are considered to be non-reactive functional groupswithin the meaning of the present invention.

Advantageously, said lubricant coating comprises a three-dimensionalsolid structure formed of cross-linked reactive functional groups of thereactive silicone and a liquid phase comprising non-reactive silicone,said liquid phase being retained within said three-dimensional solidstructure.

Non-cross-linked coatings, i.e. coatings that do not present across-linked solid network enclosing a liquid phase are outside of thescope of the invention.

According to a preferred embodiment, the amount of the non-reactivesilicone is comprised between 80 and 90% by weight relative to the totalweight of the lubricant composition.

According to a preferred embodiment, the amount of vinyl-based siliconein the lubricant composition is comprised between 8 and 15% by weightand the amount of the acrylate-based silicone in the lubricantcomposition is comprised between 2 and 5% by weight.

According to a preferred embodiment, the amount of vinyl-based siliconein the lubricant composition is 10% by weight and the amount of theacrylate-based silicone in the lubricant composition is 3% by weight.

The non-reactive silicone may be poly-(dimethylsiloxane).

The vinyl-based silicone may comprise a trimethylsilyl terminatedvinylmethylsiloxane-dimethylsiloxane copolymer.

The acrylate-based silicone may comprise a trimethylsilyl terminatedacryloxypropylmethylsiloxane-dimethylsiloxane copolymer.

Preferably, said lubricant coating has a gel structure with a gelfraction comprised between 25 and 55% by weight.

Advantageously, said lubricant coating has a shear viscosity comprisedbetween 500 and 2000 Pa·s for a shear rate of 0.1 rad/s at 25° C.

Advantageously, said lubricant coating has a phase angle comprisedbetween 20° and 40° for a shear rate of 0.1 rad/s at 25° C.

According to an embodiment, the invention provides a lubricantcomposition that can be used as an intermediate product in thefabrication of a lubricant coating for a medical container.

Said lubricant composition comprises a mixture of non-reactive siliconewith reactive silicone, wherein the reactive silicone comprises amixture of vinyl-based silicone and acrylate-based silicone.

According to a preferred embodiment, the amount of the non-reactivesilicone is comprised between 80 and 90% by weight relative to the totalweight of the lubricant composition.

According to a preferred embodiment, the amount of vinyl-based siliconein the lubricant composition is comprised between 8 and 15% by weightand the amount of the acrylate-based silicone in the lubricantcomposition is comprised between 2 and 5% by weight.

According to a preferred embodiment, the amount of vinyl-based siliconein the lubricant composition is 10% by weight and the amount of theacrylate-based silicone in the lubricant composition is 3% by weight.

The non-reactive silicone may be poly-(dimethylsiloxane).

In a preferred embodiment, the viscosity of the poly-(dimethylsiloxane)is 12500 cSt at 25° C.

The vinyl-based silicone may comprise a trimethylsilyl terminatedvinylmethylsiloxane-dimethylsiloxane copolymer.

The acrylate-based silicone may comprise a trimethylsilyl terminatedacryloxypropylmethylsiloxane-dimethylsiloxane copolymer.

According to an embodiment, the invention provides a medical containercomprising a barrel and a stopper in gliding engagement within thebarrel, wherein at least one of the barrel and the stopper is at leastpartially coated with a lubricant coating as described above.

Preferably, the thickness of the coating is of at least 350 nm.

According to an embodiment, the coating covers up to 90% of the innersurface of the barrel.

The barrel is advantageously made of plastic.

According to an embodiment, the invention provides a process formanufacturing a medical container comprising a barrel and a stopper ingliding engagement within the barrel, comprising the steps of:

-   -   depositing a lubricant composition on the inner surface of the        barrel and/or on the stopper, wherein the lubricant composition        comprises a mixture of non-reactive silicone with reactive        silicone, the reactive silicone comprising a mixture of        vinyl-based silicone and acrylate-based silicone, and    -   carrying out an irradiation of the coated barrel and/or stopper        so as to cross-link the lubricant composition to form a        lubricant coating.

According to a preferred embodiment, said irradiation comprises Gammairradiation, preferably produced by a Cobalt-60 source.

According to an embodiment, the invention provides the use of a mixtureof vinyl-based silicone and acrylate-based silicone as a reactivesilicone component in a lubricant composition comprising a mixture ofnon-reactive silicone and reactive silicone to form a lubricant coatingby cross-linking said lubricant composition, for reducing the activationforce of a stopper in gliding engagement within a barrel of a medicalcontainer, at least one of the inner surface of the barrel and/or thestopper being coated with said lubricant coating.

Preferably, the amount of vinyl-based silicone in the lubricantcomposition is comprised between 8 and 15% by weight and the amount ofthe acrylate-based silicone in the lubricant composition is comprisedbetween 2 and 5% by weight.

In an advantageous embodiment, the medical container is subjected to atleast one autoclave treatment after the formation of the lubricantcoating.

According to an embodiment, the invention provides a method of reducingthe activation and gliding forces of a stopper in gliding engagementwith a barrel of a medical container, comprising the steps of:

-   -   coating at least one of the barrel and the stopper with a        lubricant composition comprising a mixture of non-reactive        silicone and reactive silicone, the reactive silicone comprising        a mixture of vinyl-based silicone and acrylate-based silicone,        and    -   cross-linking the lubricant composition to form a coating.

According to a preferred embodiment of said method, the vinyl-basedsilicone is between 8 and 15 weight % and the acrylate-based silicone isbetween 2 and 5 weight percent relative to the total weight of thelubricant composition.

In addition, said method may further comprise subjecting the medicalcontainer to at least one autoclave treatment after the step of forminga coating.

BRIEF DESCRIPTION OF THE DRAWINGS

Other features, embodiments and advantages of the invention will beapparent from the detailed description that follows, based on theappended drawings wherein:

FIG. 1 shows a schematic view of a syringe,

FIG. 2 show a syringe barrel coated with a lubricant coating accordingto the present invention,

FIG. 3 shows the lubricant repartition on the inside surface of thebarrel along the length of the barrel,

FIG. 4 shows the evolution of the activation force of the stopper withthe number of autoclave cycles for different lubricant compositions,

FIG. 5 shows the evolution of the activation force of the stopper overtime for a composition according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

According to an embodiment of the invention, a composition for alubricant coating of a medical container comprises a mixture ofnon-reactive silicone and reactive silicone.

The coated medical container can be for example a syringe. But themedical container can also be a cartridge, an auto-injector or any otherinjection devices comprising a stopper in sliding engagement within abarrel.

As disclosed on FIG. 1, the syringe 1 comprises a barrel 2 with a flange6, the syringe being closed at its proximal end 3 by a stopper 5 and atthis distal end 4 by a cap 7.

The syringe 1 is filled with a pharmaceutical composition 8.

“Distal” means the part of the injection device the furthest from thehand of the user and the closest from the skin of the patient,“distally” meaning in the direction of the injection i.e. towards thepatient.

“Proximal” means the part of the injection device the closest from thehand of the user and the furthest from the skin of the patient,“proximally” meaning in the direction opposite to the injection i.e.towards the user.

For example, the non-reactive silicone of the coating may comprisepoly-(dimethylsiloxane) (PDMS), whose formula is:

with x between 70 and 1600.

According to a preferred embodiment, the amount of the non-reactivesilicone within the lubricant composition is in the range from 80 to 90%by weight, preferably from 85 to 90% by weight and more preferably 87%by weight.

Preferably, the viscosity of the non-reactive silicone is comprisedbetween 10 000 and 20 000 cSt at 25° C., when x is comprised between 845and 970.

According to a preferred embodiment of the invention, the viscosity ofthe non-reactive silicone is comprised between 10 000 and 15 000 cSt.

More preferably, the non-reactive silicone consists of PDMS 12 500 cStat 25° C.

For example, this non-reactive silicone is commercially available asPDMS-DC 360 from Dow Corning, Midland, USA.

In addition, the composition comprises reactive silicone, whichcomprises itself a mixture of vinyl-based silicone and acrylate-basedsilicone.

According to an advantageous embodiment, the vinyl-based silicone is acopolymer of vinylmethylsiloxane and dimethylsiloxane, withtrimethylsilyl terminations, more precisely a block copolymer ofvinylmethylsiloxane and dimethylsiloxane.

The formula of such a copolymer is for example:

with m comprised between 280 and 430, preferably 350 and n comprisedbetween 18 and 28, preferably 23.

The viscosity of this vinyl-based silicone is comprised between 800 and1200 cSt when measured at 25° C.

The amount of vinylmethylsiloxane within the copolymer is preferablybetween 7 and 8% in moles.

For example, this copolymer is commercially available from Gelest Inc,Morisville, USA under the name VDT-731, but other kind ofvinylmethylsiloxane and dimethylsiloxane copolymers can be used, asalternative, periodic or statistical vinylmethylsiloxane anddimethylsiloxane copolymers.

By contrast, non-copolymer vinyl-based silicone does not provide as goodresults as above-mentioned copolymers.

According to an advantageous embodiment, the acrylate-based silicone isa copolymer of acryloxypropylmethylsiloxane and dimethylsiloxane withtrimethylsilyl terminations.

The formula of such a copolymer is for example:

with p comprised between 60 and 80, preferably 76 and q comprisedbetween 7 and 9, preferably 8.

The viscosity of this acrylate-based silicone is comprised between 80and 120 cSt when measured at 25° C.

The amount of acryloxypropylmethylsiloxane within the copolymer ispreferably comprised between 15 and 20% in moles.

For example, this copolymer is commercially available from Gelest Inc,Morisville, USA under the name UMS-182, but other kind ofacrylatemethylsiloxane and dimethylsiloxane copolymers can be used, suchas alternative, periodic or statistical acrylatemethylsiloxane anddimethylsiloxane copolymers.

According to a preferred embodiment, the amount of the reactive siliconewithin the lubricant composition is in the range from 10 to 20% byweight and more preferably between 10 to 15% by weight.

More precisely, the weight amount of the vinyl-based silicone iscomprised from 8 to 15%, preferably from 8 to 12% and the weight amountof the acrylate-based silicone is ranging from 2 to 5%, preferably from2 to 3% by weight of the lubricant composition.

According to a preferred embodiment of the present invention, thecomposition of the coating comprises 87% of non-reactive PDMS, 10% ofvinyl-based silicone and 3% of acrylate-based silicone.

Additionally, further additives can be added in the lubricantcomposition, such as anti-oxidants, for example oxygen scavengers, UVfilters, super-absorbent agents, polymers, excipients, fibers, mineralor metallic additives or any reinforcement materials.

For preparing the lubricant composition, the three above describedcomponents are mixed together.

If necessary, the obtained mixture is maintained for degassing aftermixing, in order to remove air bubbles that may have formed duringmixing.

Such a lubricant composition is in the form of a viscous fluid that canbe applied onto the inner wall of a barrel of a medical container.

The application is usually performed at room temperature, but viscouscompositions can be applied after being submitted to heat treatment.

In an alternative embodiment, the lubricant composition can be appliedeither after the barrel has been submitted to a heat treatment ordirectly after the molding or forming of the medical container, in orderto allow a stronger adherence of this composition on the surface of thebarrel.

The lubricant composition may also be applied onto a stopper beforeinserting it within the barrel.

In such case, the lubricant composition is applied onto at least thepart of the surface of the stopper that is intended to be in contactwith the barrel, but other parts of the surface of the stopper may alsobe covered by the lubricant composition.

The application of the lubricant composition is performed with toolsthat are known per se, for example spraying devices, which will thus notbe described here in detail.

In order to provide desirable gliding properties, the thickness of thelubricant needs to be monitored.

Indeed, the thickness of the layer needs to be at least 350 nm, whenmeasured by a reflectometry method.

Further, the lubricant composition is applied so as to cover up to 90%of the barrel.

In particular, if the medical container is a syringe, it may bepreferred to apply the lubricant composition only in the center portionof the barrel, excluding both ends of the barrel.

For example, if the proximal end 3 of the barrel, located on the side ofthe plunger rod that actuates the stopper 5, is not lubricated, theremoval of the stopper may be prevented, even if the stopper is itselflubricated. Indeed, the friction force would be very high on thisnon-lubricated part of the barrel, and an important force would berequired in order to remove the stopper out of the barrel.

On the other hand, if the distal end 4 of the barrel, on the side of theinjection port, is lubricated only on a portion of the barrel length,the stopper 5 remains capable of moving towards the injection port as apart of the lubricant coating is driven by the stopper. However, it maynot be possible to move the stopper back due to consumption of thelubricant layer.

After application of the lubricant composition to the barrel and/or thestopper of a medical container, a cross-linking treatment can be carriedout in order to cross-link the lubricant composition so as to form thelubricant coating.

Preferably, the lubricant coating consists of said cross-linkedlubricant composition.

Said treatment may comprise Gamma-rays irradiation.

According to a preferred embodiment, the Gamma-rays irradiation isprovided by a Cobalt-60 source with a dose ranging from 16 to 32 kGy.

Alternatively, other kind of cross-linking treatment may be carried out,for example UV or X-Ray irradiation or plasma polymerization.

The irradiation leads to the cross-linking of the coating composition,mainly by reaction between the reactive functional groups of thevinyl-based silicone and acrylate-based silicone and it has been shownthat after irradiation the coating has a gel structure, i.e. a solidphase enclosing a liquid phase.

The composition of the coating therefore consists in a solidtridimensional molecular network of cross-linked vinyl-based andacrylate-based silicone that retains the liquid phase (corresponding tothe free, non-cross-linked silicone).

It has been shown that this unique gel structure is only present whenthe reactive silicone comprises both vinyl-based and acrylate-basedsilicone.

Contrary to a plasma treatment that would cross-link only thesuperficial layer of the composition, Gamma or UV irradiation provides asubstantially homogeneous gel structure on the whole thickness of thecoating.

It can be noted that the thickness of the layer does not change afterirradiation.

The gel structure may be defined by the following features:

-   -   a gel fraction ranging between 25 and 55% by weight, determined        by solvent swelling method (see below), and/or    -   a shear viscosity ranging from 500 to 2000 Pa·s for a shear rate        of 0.1 rad/s and at 25° C., and/or    -   a phase angle comprised between 20 and 40° for a shear rate of        0.1 rad/s and at 25° C.

The shear viscosity and the phase angle, which characterize thevisco-elastic behavior of the polymer, are measured with a rheometer.

The gel structure provides advantageous behavior of the coating both ona static and a dynamic point of view.

Indeed, the viscous part of the coating is linked to the glidingproperties, while the elastic part is involved in getting a lowactivation force.

In particular, the gel structure avoids squeeze-out of the lubricantcoating when a stopper is assembled within the barrel, with in turnreduces the activation force required to initiate movement of thestopper within the barrel; in addition, because of the visco-elasticproperties of this gel structure, a low gliding force of the stopper isobtained when it is moved along the barrel.

Furthermore, the gel structure also provides a better resistance to thecoating when submitted to autoclave.

This is particularly important because the coated container has to besubjected to at least one autoclave cycle (typically, in a saturatedsteam atmosphere at 120° C. under a pressure of 3 bars and during 20minutes) in view of its sterilization.

As shown in the comparative examples below, the addition of a smallfraction of acrylate-based silicone to a mixture of non-reactivesilicone (such as PDMS) and vinyl-based silicone provides the gelstructure after the irradiation step and the corresponding enhancedproperties of the lubricant coating.

Indeed, a lubricant composition containing only non-reactive silicone(such as PDMS) and vinyl-based silicone does not lead to a gel structureafter Co-60 irradiation.

Because of this missing tridimensional network, this lubricant coatingis liquid and is not able to resist to an autoclave cycle.

The medical container on which such a coating can be applied maycomprise a plastic or a glass barrel.

Plastic barrels are generally made of polyolefins such as high-densitypolyethylene, polypropylene, or cyclic polyolefins, or Crystal ClearPolymer.

The stopper may also be covered by a similar coating, at least on thesurface that is in contact with the barrel.

However, if the barrel is coated, it may not be necessary to apply thelubricant coating to the stopper.

Once the lubricant composition has been applied on the barrel surface,it is submitted to irradiation such as Gamma-rays irradiation in orderto cross-link the lubricant and to sterilize the barrel.

The barrel can then be filled with a liquid such as a liquidpharmaceutical composition, before being closed with a stopper to formthe medical container.

Additionally, a further sterilization step, such as UV-rays or autoclavetreatment can be performed before or after filling and closure of themedical container.

In an alternative embodiment, the barrel and the stopper can belubricated in a first step before being assembled. The medical containeris then submitted to irradiation such as Gamma-rays to achievesterilization and cross-linking of the coating. Thereafter thecorresponding medical container is filled with a liquid, such as aliquid pharmaceutical composition.

The prefilled medical container, closed by its stopper can then besterilized by autoclave treatment in a final step.

Gliding tests after two autoclave cycles have been carried out on a 50ml coated syringe filled with 50 ml of deionized water, the plasticbarrel being lubricated and the butyl rubber stopper beingnon-lubricated.

The activation and gliding forces have been measured at a speed of 100mm/min to be respectively below 30 N and 15 N.

On a chemical point of view, care must be taken to avoid extractablecomponents within the lubricant composition.

Extractable components correspond to the chemical components that may beextracted from the lubricant coating and can migrate to the liquidpharmaceutical composition contained in the medical container. Volatile,semi-volatile and non-volatile contents as well as inorganic siliconecontent have thus to be measured in this liquid pharmaceuticalcomposition.

With the medical container comprising a lubricant coating as describedabove, the extractable components are below the qualification threshold,which is currently of 5 μg/day for acrylate-based extractables.

Such chemical properties are particularly important in the case ofprefilled medical containers in order to ensure both patient's safetyand chemical stability of the pharmaceutical composition, because suchcontainers are stored over a long period of time (typically, 12 to 24months) before being used to perform an injection to a patient.

In this respect, it has been observed that a lubricant compositioncontaining only PDMS and acrylate-based silicone (with a weight ratio ofabout 25%) lead to a viscous liquid after Co-60 irradiation but alsoprovided a high extractable content, which is not acceptable.

Comparative Examples

Tests have been carried out on lubricant coating obtained fromcompositions consisting of three different silicone mixtures withdifferent percentages (by weight) of PDMS 12500 cSt, VDT-731 vinyl-basedsilicone and UMS-182 acrylate-based silicone, the F3 compositioncorresponding to an embodiment of the present invention.

Acrylate-based PDMS 12500 cSt Vinyl-based silicone silicone Composition(% by weight) (% by weight) (% by weight) F1 75 25 — F2 75 — 25 F3 87 103

Each composition has been prepared according to the protocol describedbelow.

After mixing of the different elements, each composition is degassedduring about 2 hours.

Each composition, within a range between 3.4 to 5.4 mg, is thendeposited onto the inner wall of a 50 ml barrel of Crystal Clear Polymersyringes with a siliconization bench, before submission toGamma-irradiation with a Co-60 source with a dose of 25 KGy±3 so as toform the lubricant coating.

The siliconization bench consists, in this case, in a mobile nozzle,working at an atomization and jar pressure of about 2 bars, but anyother kind of deposition methods can be used.

The same mixture as the one used to lubricate the syringes was alsopoured into a beaker to form a bulk volume (hereinafter referred to as“bulk composition”), and submitted to the same Gamma irradiation.

Then, the coated barrels are filled with water and closed with stoppersbefore being submitted to one or two autoclave cycles, each autoclavecycle being carried out at a temperature of 120° C. and a pressure of 3bars during 20 minutes.

The stoppers have not been lubricated but Gamma irradiated at a dose of25 KGy±3.

Influence of the Lubricant Repartition on the Surface of the Barrel

The repartition of the thickness T of the coating applied to the innerwall of the barrel has been measured with a RapID Layer Explorerequipment, the calibration of the equipment being done on a barrelwithout any lubricant or coating.

The thickness of the coating 9 has been measured at different distancesD from the flange 6 of the syringe 1 to the distal end 4 of the barrel 2as shown on FIG. 2.

The curve shown on FIG. 3 presents the average thickness of thelubricant deposited on four 50 ml plastic barrels measured with theRapID.

As it can be seen on the FIG. 3, the repartition of the coating is notlinear, and it has been decided to run the measurement of gliding andactivation forces for thicknesses greater than 350 nm as this is theminimum thickness required to give good stopper activation.

Mechanical Tests

Some mechanical tests have been conducted to analyze the behavior of thestopper inside the barrel for the different coatings obtained from theF1, F2 and F3 compositions, i.e. coatings F1, F2 and F3.

The test consists in measuring the activation and gliding forces of thestopper after one autoclave cycle, the activation force being defined asthe force required for putting in motion the stopper along the barrel,the gliding force being the force required for maintaining the movementof the stopper along the barrel.

To that end, a Lloyd LRX Plus bench has been used to induce the glidingof the stopper within the barrel and to measure the correspondingactivation and gliding forces.

The activation force and the gliding force have been measured at a speedof 100 mm/min

The measurements have been carried out for each coating F1, F2 and F3,each coating being applied on the barrel of two different 50 ml plasticsyringes, the syringes being filled with 50 ml of deionized water.

The results are shown in the table below.

Autoclave Purge Activation Purge gliding Coating Cycle Median Value (N)Median Value (N) F1 1 32.7 10.5 F2 1 42.9 11.8 F3 1 21.1 11.1

It can be seen from this table that the activation force issubstantially lower with a coating according to the present invention(composition F3) than with the coatings obtained from the compositionsF1 and F2.

This low value of activation force means that the stopper within abarrel lubricated with the F3 coating has a smooth initial gliding witha low stick-slip level allowing a more accurate dose delivering of thepharmaceutical composition to the patient.

FIG. 4 shows the evolution of the activation force according to thenumber of autoclave cycles submitted by the barrels coated with F1 andF3 coatings.

Indeed, the activation force for barrels coated with the F2 coating hasnot been evaluated as the activation force was already too high afterone autoclave cycle.

It can be observed on FIG. 4 that whereas the activation force increaseswith the number of autoclave cycles for the F1 coating, which isdetrimental to a smooth activation of the stopper, the activation forcewith the F3 coating is substantially stable over the autoclave cycles.

In other words, the autoclave cycles, which are required to sterilizethe medical containers, do not damage the gliding properties of thecoating according to the invention, which remains stable even after twoautoclave cycles.

Moreover, the effect of ageing has been measured for the coatingaccording to the invention. Such measurement has not been carried outfor the F1 and F2 coatings as the ageing generally causes an increase ofthe activation force. Indeed, as the activation force was initially veryhigh for these two compositions, it is obvious that the F1 and F2coating would not give satisfactory results upon ageing.

Therefore, FIG. 5 shows the evolution over time of the activation forceof a syringe coated with the F3 coating, the first measurement beingdone at t=0 (i.e. after formation of the coating by application of thecomposition and irradiation) and the second measurement being done afterone month.

It can be noted that ageing has the effect of slightly reducing theactivation force, which is favorable to the initial gliding of thestopper.

The unique formulation of the F3 composition and especially the reactivesilicone portion comprising both vinyl-based and acetate-based siliconetherefore allows optimal gliding and activation forces, even afterseveral autoclave cycles and/or extended storage time.

Gel Fraction

In another experiment, the gel percentage for the different coating F1,F2, F3 has been studied, after submission to Gamma irradiation. As theF1 coating does not have a gel structure after the Gamma irradiation, nodata have been collected for this composition. The gel fraction ismeasured on the bulk composition, whose initial weight is measured.

During this test, a solvent (namely, toluene) is mixed with the coatingduring 12 hours, in order to swell the polymer and extract the free oil.

As the F2 coating is fully extracted with toluene, resulting in asubstantially null gel fraction, the measurement of gel fraction byweight (or gel percentage) has been carried out only for the F3 coating.

Once the extraction done, the solution is filtered to collect thepolymer, and the toluene is fully evaporated in an oven during 24 hoursat 40° C.

The final weight of the dry polymer is then measured.

The gel fraction is the ratio between the final weight and the initialweight of the polymer.

For the F3 coating, the gel fraction is of about 35% by weight, as canbe seen on the next table

A significant gel fraction, meaning in a range comprised between 25 to55%, is correlated to a good resistance to squeeze-out, in particularafter autoclave treatment, as it indicates a dense tridimensional solidnetwork formed by cross-linked vinyl-based and acrylate-based siliconeenclosing the liquid non-reactive silicone.

As a result, the F3 coating with 35% of gel fraction can be consideredas a product of choice for coating.

Visco-Elastic Properties

The visco-elastic properties (shear viscosity and phase angle) have beenmeasured for each of the three F1, F2, F3 coatings when prepared as bulkcompositions.

The shear viscosity (Pa·s) measures the resistance of a system to flow,meaning how much resistant is the system to an applied shear stress.

Therefore, the shear viscosity corresponds to the polymer resistance todeformation when sheared.

The phase angle)(° relies to the ability of the system to dissipate themechanical energy into heat, knowing that the higher the phase angle is,the more dissipative the material is.

To that end, the bulk composition is loaded onto a rotational rheometer,with a gap between the lower plate and the upper plate of about 1 mm,the rheometer being rotated at frequencies between 100 and 0.1 rad/s, at25° C.

The Results with a Shear Rate of 0.1 Rad/s are Shown in the Table Below.

Nominal Shear viscosity Gel percentage Coating (Pa · s) Phase angle (°)(%) F1 N/A N/A 0 F2 465 54 0 F3 1200 35 35

As the F1 bulk coating does not have a gel structure, neither shearviscosity nor phase angle values have been measured for thiscomposition.

Regarding the other bulk coating, the F2 coating has a high phase anglemeaning that this is a highly dissipative material, with a lowresistance to an applied shear stress due to its low share viscosity,and a high squeeze-out related to a null gel percentage.

On the contrary, the F3 coating has a higher resistance to an appliedshear stress linked to its high value of shear viscosity, it is poorlydissipative as indicated by its low phase angle and it has a lowsqueeze-out correlated with a gel percentage of 35%. Therefore, theseresults confirm that the F3 coating has all the characteristics requiredto have a good gliding of a stopper inside a syringe barrel.

Indeed, it has be demonstrated that a coating with a shear viscositycomprised between 500 and 2000 Pa·s for a shear rate of 0.1 rad/s at 25°C., a phase angle comprised between 20° and 40° and a gel fractioncomprised between 25 and 55% by weight would lead to very good coatingproperties.

Chemical Tests

Extractable components have been measured on the three coating F1, F2,F3 used as a coating for a syringe after ageing of one month at 40° C.in order to analyze the comportment of the coating with time.

In particular, several analyses have been performed to assessextractables from acrylate-based silicone in the syringes, such asvolatile compounds with HS-GC/MS (acronym for Headspace-GasChromatography-Mass Spectrometry), semi-volatile compounds withLiq-GC/MS (acronym for Liquid Sample-Gas Chromatography-MassSpectrometry), non-volatile detection with UPLC-DAD (acronym for UltraHigh Performance Liquid Chromatography-Diode Array Detector),non-volatile identification with LC-Q-TOF (acronym for liquidChromatography-Quadrupole Time-Of-Flight), acidic compounds with IC(acronym for Ionic Chromatography) and elemental analysis with ICP/MS(acronym for Inductively Coupled Plasma-Mass Spectrometry).

To run such experiments, once coated, 50 ml plastic syringes have beenfilled with water, closed with rubber stoppers and tip-caps. Then, thesyringes have been autoclaved twice at 120° C. for 20 minutes, andstored for 1 month at 40° C.

In the table below are shown the concentrations and the quantities of anacrylate by-product determined by UPLC-DAD coupled with a MS/MS for thedifferent coatings F1, F2 and F3. The quantification of this by-productis important to evaluate as it could migrate in the pharmaceuticalsolution or even interact with the pharmaceutical solution itself.

By-product Average Acrylate by- Average Acrylate by- Concentrationproduct concentration product Coating (ppb) (ppb) quantity(μg/syringe)F1 N/A N/A N/A N/A N/A F2 735 522 26 593 237 F3 <LOD <LOD <LOD <LOD <LOD

As it can be seen in this table, no data have been generated for the F1coating as its composition does not contain any acrylate-based silicone.

Nevertheless, the F2 coating produces a high amount of acrylateby-products with a level of 26 μg for a syringe, which is above therecommended threshold which is around 5 μg for a 50 ml syringe while theF3 coating that corresponds to an embodiment of the invention, thequantity is below the limit of detection (LOD), which is of around 100ppb, or 5 μg.

Furthermore, it has to be noted that no extractable components has beenfound coming from the vinyl-based silicone present in the composition ofthe F1 and F3 coatings.

Therefore, the F3 coating is the product of choice for coating the innerwall of barrels as no by-product coming from acrylate or vinyl-basedsilicone would migrate into the pharmaceutical product contained intothe syringes.

Mechanical Performance

In another experiment, the coating according to the present inventionhas been studied to analyze the mechanical performances of a syringecoated from such composition after autoclave treatment and ageing.

The table below summarizes the mechanical performances of a syringecoated with the F3 coating, wherein the 50 ml barrel has been sprayedwith 4.4 mg of lubricant composition and Gamma irradiated with a dose of25 kGy±3.

Each autoclave cycle is carried out at a temperature of 120° C. and apressure of 3 bars for 20 minutes. Ageing is carried out by storage at40° C. over one month.

The median value (med) and standard deviation (stdev) of activation andgliding forces are given in the table below.

0 autoclave cycle 1 autoclave cycle 2 autoclave cycles Ageing T = 0 T =0 T = 1 month T = 0 T = 1 month Value med stdev med stdev med stdev medstdev med stdev Purge Activation 17.6 1.9 21 3 17 1.1 20.1 2.1 23.3 3.3(N) Gliding 7.4 0.8 11.1 1 8.8 0.7 10.4 1.4 8.8 0.6 (N)

As it can be seen from the table, the activation force increasesslightly after one or two autoclave cycles, with or without ageing at40° C.

It can then be concluded that the values of the activation forces remainin the same order of magnitude after autoclave and/or ageing.

Therefore, the F3 coating is very stable over time and after one or twoautoclave cycles due to its tridimensional cross-linked network.

Concerning the gliding forces, the values are also slightly increasing.

Then it can be concluded that the autoclave treatment does not impactthe gliding performance of the stopper along the wall of the barrel,meaning that the F3 coating remains stable over time despite autoclavetreatments.

In conclusion, the combination of acrylate-based and vinyl-basedsilicone as a reactive silicone component in a lubricant compositioncomprising a mixture of reactive and non-reactive silicone promotes theprovision, after irradiation, of a cross-linked lubricant coating thatexhibits a gel structure conferring reduced activation and glidingforces (even after ageing and/or autoclave treatments), with null orlimited extractable components.

While specific embodiments of the invention are described with referenceto the figures, those skilled in the art may make modifications andalterations to such embodiments without departing from the scope andspirit of the invention. Accordingly, the above detailed description isintended to be illustrative rather than restrictive. The invention isdefined by the appended claims, and all changes to the invention thatfall within the meaning and range of equivalency of the claims are to beembraced within their scope.

1. A lubricant coating for a medical container comprising a cross-linked lubricant composition comprising a mixture of non-reactive silicone and reactive silicone, wherein the reactive silicone comprises a mixture of vinyl-based silicone and acrylate-based silicone, wherein the vinyl-based silicone is between 8 and 15 weight %, and the acrylate-based silicone is between 2 and 5 weight % relative to the total weight of the lubricant composition.
 2. The lubricant coating of claim 1, wherein the non-reactive silicone is between 80 and 90 weight % relative to the total weight of the lubricant composition.
 3. The lubricant coating of claim 1, wherein the vinyl-based silicone is 10 weight % and the acrylate-based silicone is 3 weight % relative to the total weight of the lubricant composition.
 4. The lubricant coating of claim 1, wherein the non-reactive silicone is poly-(dimethylsiloxane).
 5. The lubricant coating of claim 1, wherein the vinyl-based silicone comprises a trimethylsilyl-terminated vinylmethylsiloxane-dimethylsiloxane copolymer.
 6. The lubricant coating of claim 1, wherein the acrylate-based silicone comprises a trimethylsilyl-terminated acryloxypropylmethylsiloxane-dimethylsiloxane copolymer.
 7. The lubricant coating of claim 1, wherein the lubricant composition has a gel structure, the gel structure comprising a three-dimensional solid structure formed of cross-linked reactive functional groups of the reactive silicone and a liquid phase comprising non-reactive silicone, the liquid phase being retained within the three-dimensional solid structure.
 8. The lubricant coating of claim 1, wherein the lubricant composition has a gel structure comprising a gel fraction of between 25 and 55 weight %.
 9. The lubricant coating of claim 1, having a shear viscosity between 500 and 2,000 Pa·s for a shear rate of 0.1 rad/s at 25° C.
 10. The lubricant coating of claim 1, having a phase angle between 20° and 40° for a shear rate of 0.1 rad/s at 25° C.
 11. A lubricant composition for a medical container comprising a mixture of non-reactive silicone with reactive silicone, wherein the reactive silicone comprises a mixture of vinyl-based silicone and acrylate-based silicone, wherein the vinyl-based silicone is between 8 and 15 weight %, and the acrylate-based silicone is between 2 and 5 weight % relative to the total weight of the lubricant composition.
 12. The lubricant composition of claim 11, wherein the non-reactive silicone is between 80 and 90 weight % relative to the total weight of the lubricant composition.
 13. The lubricant composition of claim 11, wherein the vinyl-based silicone is 10 weight %, and the acrylate-based silicone is 3 weight % relative to the total weight of the lubricant composition.
 14. The lubricant composition of claim 11, wherein the non-reactive silicone is poly-(dimethylsiloxane).
 15. The lubricant composition of claim 14, wherein the viscosity of the poly-(dimethylsiloxane) is 12,500 cSt at 25° C.
 16. The lubricant composition of claim 11, wherein the vinyl-based silicone comprises a trimethylsilyl terminated vinylmethylsiloxane-dimethylsiloxane copolymer.
 17. The lubricant composition of claim 11, wherein the acrylate-based silicone comprises a trimethylsilyl terminated acryloxypropylmethylsiloxane-dimethylsiloxane copolymer.
 18. A method of manufacturing a medical container comprising a barrel having an inner surface and a stopper in gliding engagement with at least a portion of the inner surface of the barrel, comprising the steps of: depositing a lubricant composition on at least one of the inner surface of the barrel and the stopper, wherein the lubricant composition comprises a mixture of non-reactive silicone with reactive silicone, the reactive silicone comprising a mixture of vinyl-based silicone and acrylate-based silicone, wherein the vinyl-based silicone is between 8 and 15 weight %, and the acrylate-based silicone is between 2 and 5 weight % relative to the total weight of the lubricant composition, and irradiating at least one of the barrel and the stopper so as to cross-link the lubricant composition to form a lubricant coating.
 19. The method of claim 18, wherein the step of irradiating comprises using Gamma irradiation.
 20. The method of claim 19, wherein the Gamma irradiation is produced by a Cobalt-60 source.
 21. The method of claim 18, wherein the method further comprises subjecting the medical container to at least one autoclave treatment after the step of forming a coating. 